Surgical Management of Spinal Disorders in People with Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of inherited, multisystem, lysosomal storage disorders involving specific lysosomal enzyme deficiencies that result in the accumulation of glycosaminoglycans (GAG) secondary to insufficient degradation within cell lysosomes. GAG accumulation affects both primary bone formation and secondary bone growth, resulting in growth impairment. Typical spinal manifestations in MPS are atlantoaxial instability, thoracolumbar kyphosis/scoliosis, and cervical/lumbar spinal canal stenosis. Spinal disorders and their severity depend on the MPS type and may be related to disease activity. Enzyme replacement therapy or hematopoietic stem cell transplantation has advantages regarding soft tissues; however, these therapeutic modalities are not effective for bone or cartilage and MPS-related bone deformity including the spine. Because spinal disorders show the most serious deterioration among patients with MPS, spinal surgeries are required although they are challenging and associated with high anesthesia-related risks. The aim of this review article is to provide the current comprehensive knowledge of representative spinal disease in MPS and its surgical management, including the related pathology, symptoms, and examinations.

Download Full-text

Mucopolysaccharidoses and Orthopedic Management (Focused also on Craniocervical Junction)

Journal of Child Science ◽

10.1055/s-0038-1669384 ◽

2018 ◽

Vol 08 (01) ◽

pp. e128-e137

Author(s):

Christina Lampe ◽

Christian Lampe

Keyword(s):

Spinal Cord ◽

Soft Tissues ◽

Surgical Intervention ◽

Cervical Spinal Cord ◽

Joint Stiffness ◽

Craniocervical Junction ◽

Musculoskeletal Symptoms ◽

Atlantoaxial Instability ◽

Enzyme Replacement ◽

Life Threatening

AbstractMucopolysaccharidoses (MPSs) are multisystemic, chronic progressive, heterogeneous, and life-threatening diseases, involving severely the musculoskeletal system, in particular in MPS I, II, IV, VI, VII, and less prevalent in MPS III. Accumulation of glycosaminoglycans (GAGs) in soft tissues, such as ligaments, tendons, and joint capsules, as well as in cartilage, and bone lead to orthopedic complications: joint stiffness, contractures, and skeletal deformities, resulting in hip dysplasia, genua valga, feet deformities, kyphoscoliosis, narrowing of the spinal canal, atlantoaxial instability, carpal tunnel syndrome, trigger finger, and growth retardation. These complications significantly reduce the quality of life due to impaired mobility, loss of independency, and pain. Compression of the cervical spinal cord is also life threatening. According to the progressive nature of MPSs, musculoskeletal symptoms worsen over time and surgical intervention may be inevitable. However, due to the increased anesthesia risk of MPSs, surgical intervention has to be evaluated carefully by a multidisciplinary team. Additionally, due to the rarity of the diseases, not many standards or recommendations are available to determine the indication of a surgical intervention, so each intervention must be decided individually, based on the few data available. In addition, conservative treatment should be taken into consideration. Physiotherapy, pain medication, insoles, orthosis, braces, corsets, and special footwear play a pivotal role. Unfortunately, the skeletal tissues are poorly vascularized and enzyme replacement therapy does not have much effect on them. It is important to detect and observe musculoskeletal complications in the regular follow-up visits, in particular the life-threatening compression of the cervical spinal cord.

Download Full-text

Mucopolysaccharidoses

Musculoskeletal Imaging Volume 2 ◽

10.1093/med/9780190938178.003.0084 ◽

2019 ◽

pp. 79-82

Author(s):

Kevin B. Hoover

Keyword(s):

Stem Cell ◽

Soft Tissues ◽

Lysosomal Storage Diseases ◽

Appendicular Skeleton ◽

Lysosomal Storage ◽

Storage Diseases ◽

Enzyme Replacement ◽

Mps Ii ◽

Spine Mri ◽

Mps I

Chapter 84 discusses mucopolysaccharidoses, which are genetic, lysosomal storage diseases resulting in the accumulation of glycosaminoglycans (GAG) in the soft tissues. Musculoskeletal complications of mucopolysaccharidosis (MPS) are common beginning in childhood. These result from abnormal ossification and periarticular GAG accumulation. Radiographs of the axial and appendicular skeleton (skeletal survey) are used for the baseline assessment of MPS disease. Progression of skeletal abnormalities is monitored with annual cervical spine MRI. Stem cell transplantation is the treatment of choice in MPS I, and enzyme replacement therapy (ERT) is the treatment of choice in MPS I Hurler-Scheie and Scheie, MPS II, and MPS VI.

Download Full-text

Ophthalmological Findings in Mucopolysaccharidoses

Journal of Clinical Medicine ◽

10.3390/jcm8091467 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1467 ◽

Cited By ~ 5

Author(s):

Shizuka Tomatsu ◽

Susanne Pitz ◽

Ulrike Hampel

Keyword(s):

Focal Point ◽

Childhood Mortality ◽

Research Progress ◽

Type I ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Ocular Manifestations ◽

Corneal Clouding ◽

Low Incidence

The mucopolysaccharidoses (MPS) are a heterogenous group of lysosomal storage disorders caused by the accumulation of glycosaminoglycans (GAGs). The accrual of these compounds results in phenotypically varied syndromes that produce multi-organ impairment with widespread systemic effects. The low incidence of MPS (approximately 1/25,000 live births) in conjunction with the high childhood mortality rate had limited the availability of research into certain clinical features, especially ocular manifestations. As the recent successes of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) have greatly increased life expectancy in these patients, they have served as a focal point for the transition of research towards improvement of quality of life. Ophthalmological findings in MPS include corneal clouding, glaucoma, optic neuropathies, and retinopathies. While corneal clouding is the most common ocular feature of MPS (especially type I, IVA, and VI), its response to HSCT and ERT is minimal. This review discusses known eye issues in the MPS subtypes, diagnosis of these ocular diseases, current clinical and surgical management, noteworthy research progress, and ultimately presents a direction for future studies.

Download Full-text

Wolman's Disease: A Rare Cause of Infantile Cholestasis and Cirrhosis

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715119 ◽

2020 ◽

Author(s):

Jagadeesh Menon ◽

Naresh Shanmugam ◽

Sripriya Srinivas ◽

Mukul Vij ◽

Anil Jalan ◽

...

Keyword(s):

Metabolic Disorders ◽

Lysosomal Storage ◽

Acid Lipase ◽

Hematopoietic Stem ◽

X Ray ◽

Enzyme Replacement ◽

Lipase Enzyme ◽

Advanced Cirrhosis ◽

Infantile Cholestasis ◽

Diagnostic Clue

AbstractLiver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

Download Full-text

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

Diagnostics ◽

10.3390/diagnostics9040195 ◽

2019 ◽

Vol 9 (4) ◽

pp. 195 ◽

Cited By ~ 2

Author(s):

Iskren Menkovic ◽

Anne-Sophie Marchand ◽

Michel Boutin ◽

Christiane Auray-Blais

Keyword(s):

Dermatan Sulfate ◽

Absolute Quantification ◽

Urine Samples ◽

Cell Transplant ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Urine Screening ◽

Enzyme Replacement ◽

System A ◽

Relative Standard

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays the onset of symptoms, highlighting the need for newborn screening for MPSs. The main objective of this project was to devise and validate a multiplex urine filter paper method for GAG analysis using a tandem mass spectrometry (MS/MS) approach to screen newborns for MPSs. Eluted urine samples from 21-day-old newborns were evaporated and a methanolysis reaction was performed. Samples were resuspended and analyzed using a UPLC-MS/MS system. A one-minute chromatographic method allowed the absolute quantification of heparan sulfate (HS), dermatan sulfate (DS), and creatinine. Method validation revealed high precision (< 9% relative standard deviation) and accuracy (< 7% bias) for all analytes. The reference values normalized to creatinine obtained by the analysis of five hundred 21-day-old newborn urine samples were 34.6 +/-6.2 mg/mmol of creatinine and 17.3 +/-3.9 mg/mmol of creatinine for HS and DS, respectively. We present a rapid and efficient method for populational newborn urine screening using MS/MS, which could also be applied to high-risk screening.

Download Full-text

Congenital metabolic diseases. Lysosomal storage diseases

Pediatrician (St Petersburg) ◽

10.17816/ped12273-83 ◽

2021 ◽

Vol 12 (2) ◽

pp. 73-83

Author(s):

Victoria N. Gorbunova

Keyword(s):

Metabolic Disorders ◽

Lysosomal Storage Diseases ◽

Cellular Damage ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Storage Diseases ◽

Enzyme Replacement ◽

Total Incidence ◽

Organ Systems ◽

Monogenic Diseases

The classification and epidemiology of hereditary metabolic disorders are presented. That is a large group consisting from more them 800 monogenic diseases, each of which caused by inherited deficiency of certain metabolic fate. Many of these disorders are extremely rare, but their total incidence in the population is close to 1:10005000. Lysosomal storage diseases (LSD) resulting from inherited deficiency in lysosomal functions occupy a special place among hereditary metabolic disorders. The defects of catabolism cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, storage), which can result in cellular damage. About 60 diseases take part in this group with total incidence of about 1:70008000. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most of them have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. The etiology and pathogenetic aspects of their main clinical entities: mucopolysaccharidosis, glycolipidosis, mucolipidosis, glycoproteinosis, etc, are presented. Mucopolysaccharidoses caused by malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans are more frequent among LSD. Sphingolipidoses caused by defects of lipid catabolism are second for frequency group of LSD. The state-of-art in field of newborn screening. clinical, biochemical and molecular diagnostics of these grave diseases are discussed. The main directions of modern lysosomal storage diseases therapy are characterized: transplantation of hematopoietic stem cells; enzyme replacement therapy; therapy with limitation of substrate synthesis (substrate-reducing therapy); pharmacological chaperone therapy. Perspective directions for LSD therapy are gene therapy and genome editing which are at advanced preclinical stages.

Download Full-text

First Report of a Patient with MPS Type VII, Due to Novel Mutations in GUSB, Who Underwent Enzyme Replacement and Then Hematopoietic Stem Cell Transplantation

International Journal of Molecular Sciences ◽

10.3390/ijms20215345 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5345 ◽

Cited By ~ 3

Author(s):

Patricia Dubot ◽

Frédérique Sabourdy ◽

Geneviève Plat ◽

Charlotte Jubert ◽

Claude Cancès ◽

...

Keyword(s):

Enzyme Activity ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Cellular Therapy ◽

Psychomotor Development ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Double Mutation ◽

Enzyme Replacement ◽

Skin Infiltration

We report the case of a boy who was diagnosed with mucopolysaccharidosis (MPS) VII at two weeks of age. He harbored three missense β-glucuronidase (GUSB) variations in exon 3: two novel, c.422A>C and c.424C>T, inherited from his mother, and the rather common c.526C>T, inherited from his father. Expression of these variations in transfected HEK293T cells demonstrated that the double mutation c.422A>C;424C>T reduces β-glucuronidase enzyme activity. Enzyme replacement therapy (ERT), using UX003 (vestronidase alfa), was started at four months of age, followed by a hematopoietic stem cell allograft transplantation (HSCT) at 13 months of age. ERT was well tolerated and attenuated visceromegaly and skin infiltration. After a severe skin and gut graft-versus-host disease, ERT was stopped six months after HSCT. The last follow-up examination (at the age of four years) revealed a normal psychomotor development, stabilized growth curve, no hepatosplenomegaly, and no other organ involvement. Intriguingly, enzyme activity had normalized in leukocytes but remained low in plasma. This case report illustrates: (i) The need for an early diagnosis of MPS, and (ii) the possible benefit of a very early enzymatic and/or cellular therapy in this rare form of lysosomal storage disease.

Download Full-text

Lysosomal Storage Disorders

10.1093/med/9780199937837.003.0068 ◽

2017 ◽

Author(s):

Gustavo H. B. Maegawa

Keyword(s):

Molecular Mechanisms ◽

Substantial Improvement ◽

Lysosomal Storage Disorders ◽

Substrate Reduction Therapy ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Psychiatric Disturbances ◽

Extrapyramidal Signs ◽

Storage Disorders

The lysosomal storage disorders (LSDs) are a group of inborn organelle disorders, clinically heterogeneous, and biochemically characterized by accumulation of nondegraded macromolecules primarily in the lysosomal and other cellular compartments. Given the common and essential cellular function of the lysosomal system in different organs and systems, patients afflicted with these disorders present a broad range of clinical problems, including neurological problems, visceromegaly, and skeletal deformities. Onset of symptoms may range from fetal period to adulthood. The neurological problems include developmental delay, seizures, acroparesthesia, motor weakness, muscle wasting, behavioral/psychiatric disturbances, cerebrovascular ischemic events, and extrapyramidal signs. Patients may present with symptoms later that include psychiatric manifestations, are slowly progressive, and may precede other neurologic or systemic features. Most of LSDs are autosomal recessive; however, a few are X-linked with symptpmatic female carriers (e.g., Fabry disease). In most of them, the diagnosis is established by biochemical and/or molecular assays. In terms of management, disease-modifying therapies include enzyme replacement, hematopoietic stem cell transplantation, and substrate reduction therapy. Patients and their families require genetic counseling regarding reproductive risks, disease prognosis, and therapeutic options. Investigations of disease molecular mechanisms provide insights into potential targets for the development of therapeutic strategies. Supportive care has been the key and essential for most LSDs, resulting in substantial improvement in quality of life of patients and families.

Download Full-text

O27: MICROGLIAL CORRECTION AFTER FETAL THERAPY WITHOUT CONDITIONING IN MICE WITH MUCOPOLYSACCHARIDOSIS TYPE VII

British Journal of Surgery ◽

10.1093/bjs/znab117.027 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

Quoc-Hung Nguyen ◽

Russell G Witt ◽

Wang Bowen ◽

Carlo Eikani ◽

Jeremy Shea ◽

...

Keyword(s):

Flow Cytometry ◽

Rna Sequencing ◽

In Utero ◽

Gus Activity ◽

Brain Inflammation ◽

Treatment Modalities ◽

Mucopolysaccharidosis Type ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Enzyme Replacement

Abstract Introduction Mucopolysaccharidosis type 7 (MPS7) is a lysosomal storage disorder typically fatal in utero. Postnatal enzyme replacement therapy (ERT) to replace missing glucuronidase (GUS) does not penetrate the blood-brain barrier (BBB). We investigated whether in utero ERT (IUERT) specifically targets brain microglia (natural GUS storehouses and key brain inflammation mediators) and whether in utero hematopoietic stem cell transplantation (IUHSCT) results in microglial engraftment as a strategy for permanent correction. Methods We performed IUERT by injecting GUS into MPS7 fetuses mid-gestation, and analyzed tissue homogenates (via colorimetric substrate) and brain microglia (via flow cytometry) for enzyme activity after 4-7 days. We performed IUHSCT by transplanting HSCs mid-gestation from CX3CR1-GFP donors. We examined blood, bone marrow, and brain for engraftment. We assessed brain inflammation by staining for CD68. We performed RNA sequencing to characterize engrafted microglia. Results IUERT resulted in detectable brain GUS activity. Flow cytometry showed that GUS activity after IUERT was near wild-type levels, and brains harvested in adulthood had decreased inflammation via CD68 immunohistochemistry. IUHSCT resulted in multilineage engraftment of hematopoietic cells in blood and bone. Confocal microscopy revealed multifocal engraftment of donor-derived microglia. RNA sequencing indicated that engrafted microglia were nearly identical to endogenous microglia. MPS7 chimeras had evidence of reduced brain inflammation near donor microglia. Conclusion Both IUERT and IUHSCT are complementary treatment modalities that can penetrate the BBB and ameliorate neurologic manifestations of diseases such as MPS7. These results lay the foundation for future studies using in utero molecular therapies for MPS7 as well as other storage disorders.

Download Full-text